Long-term and Preventative Treatment in SAD - Mood Disorders

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2007, Vol. 21, No. 11 (pp. 901-909) ISSN: 1172-7047

Therapy In Practice Long-Term and Preventative Treatment for SAD

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THERAPY IN PRACTICE

 2007 Adis Data Information BV. All rights reserved.

Long-Term and Preventative Treatment for Seasonal Affective Disorder ˚ Westrin1 and Raymond W. Lam2 Asa 1 2

Department of Clinical Sciences, Division of Psychiatry, Lund University Hospital, Lund, Sweden Division of Clinical Neuroscience, Department of Psychiatry, University of British Columbia (UBC), Vancouver, British Columbia, Canada

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 901 1. Longer Term Treatment Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903 2. Maintenance and Prevention Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903 3. Clinical Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907

Abstract

Recurrent major depressive disorder with regular seasonal patterns, commonly known as seasonal affective disorder (SAD), has evoked substantial research in the last two decades. It is now recognised that SAD is a common condition with prevalence rates between 0.4% and 2.9% of the general population, and that patients with SAD experience significant morbidity and impairment in psychosocial function. There is good evidence that bright light therapy and antidepressant medications are effective for the short-term treatment of SAD; however, given that SAD is characterised by recurrent major depressive episodes, long-term and maintenance treatment must be considered. Unfortunately, there are few studies of longer term (>8 weeks) and maintenance (preventative) treatments for SAD. The weight of evidence suggests that light therapy usually needs to be continued daily throughout the winter season because of rapid relapse when light is stopped too early in the treatment period. However, some studies support the use of antidepressants to continue the response from a brief (1–2 weeks) course of light therapy early in the depressive episode, as soon as the first symptoms emerge in autumn. Only small studies have examined preventative treatment (before onset of symptoms) with light therapy, all of which have methodological limitations. The best evidence for preventative treatment in SAD comes from antidepressant studies. Three large, randomised, placebo-controlled studies have shown that preventative treatment with bupropion XL reduces the recurrence rate of depressive episodes in patients with SAD.

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Given the limitations in the evidence base and the inconsistent recurrence rate of winter depressive episodes, clinical recommendations for long-term and preventative treatment must individualise treatment choices and weigh potential benefits against possible adverse effects.

The DSM-IV describes seasonal affective disorder (SAD) as “recurrent major depressive episodes with regular seasonal patterns”.[1] Such episodes occur most commonly during autumn and winter, and remit (or switch to hypomania or mania) during spring and summer.[2] Some patients with SAD may experience nonseasonal depressive episodes during their lifetime, but these are substantially less frequent than the seasonal episodes. SAD is also associated with so-called atypical depressive symptoms, including hypersomnia, increased appetite and eating, carbohydrate craving and weight gain.[3] SAD is a relatively common condition. Epidemiological studies, based on diagnostic interviews and DSM criteria, found prevalence rates for this disorder in the general population of 0.4% in the US[4] and 1.7–2.9% in Canada.[5,6] Other studies, using self-report questionnaires, have shown community prevalence rates for SAD ranging from 10%.[3] The aetiology of SAD remains unknown, but major theories of the pathophysiology of this disorder include circadian hypotheses, neurotransmitter dysfunction hypotheses and genetic hypotheses.[7,8] The depressive symptoms in SAD result in significant morbidity and impairment in psychosocial function. Patients with seasonal depression in a primary care clinic were found to have greater functional impairment than those with many other common medical conditions.[9] Both social adjustment and quality of life in patients with SAD were significantly worse than in nondepressed community samples, with impairment comparable to patients with nonseasonal major depressive disorder.[10,11] The progressive weight gain experienced by many patients with SAD may also lead to greater risk for obesity, diabetes and the metabolic syndrome.[12] The treatment of SAD is focused on light therapy (daily exposure to bright, artificial light)[13] and

antidepressant medications.[14] Despite some methodological issues in designing appropriate placebo conditions, several systematic reviews and metaanalyses have shown that light therapy is an effective short-term treatment for SAD.[15,16] The most recent meta-analysis found a large effect size of 0.84 (95% CI 0.6, 1.08) for bright light therapy compared with control conditions.[16] Similarly, while there are fewer studies of antidepressants in the short-term treatment of SAD, randomised controlled trials (RCTs) of SSRIs, such as fluoxetine (20 mg/day)[17] and sertraline (50–200 mg/day),[18] have shown evidence for efficacy in this disorder. Comparative studies and smaller, open-label studies suggest that other antidepressants, such as bupropion, reboxetine and moclobemide, may also be effective.[19-22] A direct comparison study has shown that light therapy and fluoxetine have similar effectiveness in SAD,[23] but unfortunately there are no studies of combination light and medication treatment.



These studies have all addressed the short-term treatment of SAD.[15-23] In the management of depression, we now recognise that there are also continuation and/or maintenance phases of treatment in which the objectives of care are to prevent relapse and recurrence.[24,25] In fact, most clinical practice guidelines recommend long-term maintenance treatment to prevent depressive episodes in recurrent depression.[26-28] Since SAD, by definition, is a recurrent depressive condition, longer term studies (i.e. through a full winter season) and maintenance or prophylactic treatment studies (to prevent future depressive episodes) are very important. In this article, we review the evidence for longer term and prophylactic treatment of SAD, focusing on randomised trials or observational studies with larger sample sizes, and provide clinical strategies for prevention of depressive episodes.

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Long-Term and Preventative Treatment for SAD

1. Longer Term Treatment Studies A major problem with light therapy acute treatment studies is their short duration of treatment, with placebo-controlled studies ranging from 1 to 5 weeks in duration.[15,16] The short-term antidepressant trials and the comparative light versus fluoxetine study were also only 8 weeks in length.[17,18,23] Few studies have examined treatment for >8 weeks over the course of the 4–6 month fall/winter season. One exception is a 14-week, open-label study of agomelatine, a novel antidepressant with melatonin MT1 and MT2 receptor agonist and serotonin 5-HT2C receptor antagonist properties.[29] Thirtyseven outpatients with SAD, as defined by DSMIV-TR, and meeting criteria for a moderate to severe depressive episode, were recruited between the first week of October and the second week of December. Patients with a baseline score of ≥22 on the 29-item version of the Structured Interview Guide for the Hamilton Depression Rating Scale (SAD version; SIGH-SAD) were treated with agomelatine 25 mg/ day for 14 weeks. The SIGH-SAD scores improved significantly from week 2 onwards, and after 14 weeks 76% of the patients had responded to treatment (defined as >50% reduction of total SIGHSAD score) and 70% reached the remission criteria (SIGH-SAD score 700nm, 0.18 lux, 30 min daily) throughout winter No light treatment

38

RCT Treatments started before onset of symptoms Patients followed through one winter

Recurrence rates were significantly lower in the infrared light group (33%) compared with placebo (66%) No difference between bright light (43%) and infrared light (33%) conditions

Modell et al.[43] (2005)

Bupropion XL (150–300 mg/day) throughout winter Placebo

RCT, three studies with identical design Treatments started before onset of symptoms Patients followed through one winter

Recurrence rates significantly lower in the bupropion-treated group (16%) compared with placebo (28%)

Lingaerde et al.[44] (1999)

Ginkgo biloba 120 mg/day for 10 weeks Placebo

RCT Treatments started before onset of symptoms Patients followed for 10wk

No significant differences between groups in the recurrence of depressive episodes or key mood symptoms

1042 (pooled sample)

27

905

RCT = randomised controlled trial.

Sample size (n)


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Table I. Studies on the prevention of depressive episodes in seasonal affective disorder

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bupropion XL 150 mg/day or placebo for the first week, following which those receiving bupropion XL were increased to 300 mg/day (if the 300 mg/day dosage was not tolerated, it could be reduced to 150 mg/day). In the first week of spring, the dosage was reduced to 150 mg/day for 2 weeks and then discontinued, after which the patients were followed off medication by telephone interviews for 8 weeks. A recurrence of a depressive episode was defined as a SIGH-SAD ≥20, or fulfilling DSM-IV criteria for major depressive episode. Results for the three individual studies, as well as a pooled analysis since the study designs were identical, are summarised in figure 1. Recurrence rates were significantly lower for the bupropion XL group than for the placebo group in all three studies (19% vs 30% for study A, 13% vs 21% for study B, 16% vs 31% for study C and 16% vs 28% for the pooled sample, respectively). However, survival analyses for time to onset of depression, comparing bupropion XL with placebo, only reached significance in study C and in the pooled sample. Furthermore, it should be noted that the recurrence rates of depressive episodes were low overall, even in the placebotreated groups.

of dry mouth, nausea, constipation and flatulence than placebo. Together, these three studies provide good evidence for the efficacy and tolerability of bupropion XL as a preventative treatment for depressive episodes of SAD when commenced before the onset of symptoms. Of interest is that this is the only SAD study examining discontinuation of treatment in the spring. In the 8-week follow-up after bupropion was stopped, there was no evidence for discontinuationemergent adverse events. Additionally, depression recurrence rates after stopping medications were very low and no different than placebo (2.7% and 2.1%, respectively). This indicates that medication can be successfully discontinued during the spring and summer months. Finally, some studies with small sample sizes have investigated novel treatments for prevention. In an RCT (n = 27), the herbal remedy ginkgo biloba did not differ from placebo as a preventative treatment for SAD.[44] Another study randomised 23 patients with SAD to 6 weeks of treatment with light therapy, a group-based cognitive behaviour therapy (CBT) intervention, and the combination of light therapy and CBT, and then examined outcomes during the subsequent winter season.[45] All three treatments demonstrated significant but similar responses in the short-term treatment trial. However, at naturalistic follow-up during the subsequent winter, patients who had CBT, particularly in combination with light therapy, had better outcomes, as measured by symptom severity, remission rates and relapse rates. This was not a true prevention trial because of the naturalistic follow-up in which patients were allowed to use other treatments, but it suggests that CBT may offer some benefits beyond the short-term treatment phase, in the same way that CBT may help prevent episodes of nonseasonal depression.

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. Recurrence of seasonal MDE (%)

In these studies, dropout rates for any reason (24% vs 22%) and because of adverse events (9% vs 5%) did not differ between bupropion and placebo. Frequencies of adverse events were low overall, with bupropion showing slightly higher frequency 50

Bupropion XL (150–300 mg/day) Placebo

45 40 35

p < 0.001

p < 0.03

30 25

p < 0.0001

p < 0.05

20 15 10

3. Clinical Recommendations

5 0 Study A (n = 272)

Study B (n = 306)

Study C (n = 464)

Pooled (n = 1042)

Fig. 1. Bupropion XL vs placebo in the prevention of seasonal major depressive episodes (MDE) in seasonal affective disorder (reproduced from Modell et al.,[43] with permission).


Seasonal depression is a common and recurrent condition that causes significant morbidity and impairment of psychosocial function, therefore it is reasonable to consider prophylactic and mainteCNS Drugs 2007; 21 (11)


nance treatments to prevent depressive episodes. Complicating the issue, however, is the fact that some patients, even with a history of consecutive winter depressive episodes, may not experience a depressive episode in any particular winter. Unfortunately, there are still limited data to guide clinical recommendations for the prevention of SAD. Therefore, the decision to use a preventative treatment must take into account a variety of factors, including individual course and severity of illness, predictability of episodes and their onset, patient preference and motivation, and availability of resources. Similarly, the choice of preventative treatment requires individual assessment to weigh potential benefits against risks of adverse effects. For example, light therapy may be the treatment of choice for patients who prefer nonpharmacological treatment, have relative contraindications to drug therapy (e.g. hepatic disease) or are intolerant to medication adverse effects. On the other hand, medication treatment may be the treatment of choice for patients who cannot make the time commitment for light therapy, have relative contraindications to light therapy (e.g. retinal disease, macular degeneration, use of photosensitising medications) or are intolerant to the adverse effects of bright light.

907

Better evidence exists for the preventative efficacy of antidepressants, but only bupropion XL has been adequately studied and approved for the prevention of episodes of SAD by regulatory agencies (in the US). It is certainly possible that other antidepressants (e.g. SSRIs such as fluoxetine and sertraline, which show efficacy in short-term treatment) are also effective. For antidepressants, preventative treatment should be started in the early autumn at least 4 weeks (the typical time period for response to medications) prior to the usual onset of symptoms. Extrapolating from the results of the bupropion XL studies, it appears that antidepressants can be safely tapered and discontinued in the spring (at the time of usual remission) and summer. Discontinuation symptoms, however, may vary among different antidepressants and it is important to distinguish these from depressive symptoms, indicating recurrence. It may be more prudent to continue the antidepressant year-round for individual patients if they have usual remission of symptoms later in the spring, require longer taper periods (e.g. those on higher doses or those who experience significant discontinuation symptoms), or have subsyndromal symptoms in the summer, as the time off medication will be very short. In this situation, patients should be cautioned about the possibility of spring/summer hypomania. In clinical practice it is also common to combine light and antidepressant treatment.[46] Unfortunately, no studies have examined the effect of combination use of light therapy and antidepressants, either for short-term or maintenance treatment. In addition, there is a suggestion that CBT may also offer benefits for the prevention of SAD. These will be important future research directions for the field.

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. There are only limited efficacy data for longer term and preventative treatment with light therapy. Because light therapy has a fast onset of action (from a few days to 1 or 2 weeks), it is reasonable to recommend starting light therapy at the time of first onset of symptoms in the autumn; however, some patients have rapid onset of symptoms or may not recognise the insidious onset of depression until they are in a full episode. These patients may want to restart their light therapy at least 2 weeks (the typical time period for response to light) ahead of their usual onset of depressive symptoms. There is no good evidence that a brief course of light therapy can prevent relapse, therefore light treatment should be continued throughout the winter season and discontinued during spring and summer. Alternatively, a brief course of light treatment can be followed by continuation treatment with antidepressant medication through the winter months.  2007 Adis Data Information BV. All rights reserved.

4. Conclusions

Longer term and preventative treatments for patients with SAD are indicated because of the duration and recurrent pattern of winter depressive episodes. Unfortunately, there is less evidence for efficacy of light therapy and antidepressants in continuation and maintenance phases than for acute treatment of SAD. Hence, clinical recommendations CNS Drugs 2007; 21 (11)

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are based on a limited number of quality studies and by extrapolating from acute studies. A complicating factor is the variable predictability of self-reported seasonal patterns of illness, since prospective monitoring indicates that only about 30–70% of patients with SAD will have recurrence of a winter depressive episode. Therefore, the need for, and choice of preventative treatment relies on clinical judgement and consideration of various factors, including individual course and severity of illness, predictability of episodes and their onset, patient preferences and motivation, and availability of resources. Given the significant personal and psychosocial impairment associated with SAD, it is important to conduct further studies to determine which patients need maintenance treatment and how to optimise preventative treatment with light therapy and/or antidepressants.

6. Levitt AJ, Boyle MH. The impact of latitude on the prevalence of seasonal depression. Can J Psychiatry 2002; 47 (4): 361-7 7. Sohn CH, Lam RW. Update on the biology of seasonal affective disorder. CNS Spectr 2005; 10 (8): 635-46 8. Lam RW, Levitan RD. Pathophysiology of seasonal affective disorder: a review. J Psychiatry Neurosci 2000; 25 (5): 469-80 9. Schlager D, Froom J, Jaffe A. Winter depression and functional impairment among ambulatory primary care patients. Compr Psychiatry 1995; 36 (1): 18-24 10. Pendse BP, Ojehagen A, Engstrom G, et al. Social characteristics of seasonal affective disorder patients: comparison with suicide attempters with non-seasonal major depression and other mood disorder patients. Eur Psychiatry 2003; 18 (1): 36-9 11. Michalak EE, Wilkinson C, Hood K, et al. Seasonality, negative life events and social support in a community sample. Br J Psychiatry 2003; 182: 434-8 12. McElroy SL, Kotwal R, Malhotra S, et al. Are mood disorders and obesity related? A review for the mental health professional. J Clin Psychiatry 2004; 65 (5): 634-51 13. Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr 2005; 10 (8): 647-63 14. Pjrek E, Winkler D, Kasper S. Pharmacotherapy of seasonal affective disorder. CNS Spectr 2005; 10 (8): 664-9 15. Thompson C. Evidence-based treatment. In: Partonen T, Magnusson A, editors. Seasonal affective disorder: practice and research. New York; Oxford University Press, 2001: 151-8 16. Golden RN, Gaynes BN, Ekstrom RD, et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. Am J Psychiatry 2005; 162 (4): 656-62 17. Lam RW, Gorman CP, Michalon M, et al. Multicenter, placebocontrolled study of fluoxetine in seasonal affective disorder. Am J Psychiatry 1995; 152 (12): 1765-70 18. Moscovitch A, Blashko CA, Eagles JM, et al. A placebocontrolled study of sertraline in the treatment of outpatients with seasonal affective disorder. Psychopharmacology (Berl) 2004; 171 (4): 390-7 19. Hilger E, Willeit M, Praschak-Rieder N, et al. Reboxetine in seasonal affective disorder: an open trial. Eur Neuropsychopharmacol 2001; 11 (1): 1-5 20. Lingjaerde O, Reichborn-Kjennerud T, Haggag A, et al. Treatment of winter depression in Norway: II. A comparison of the selective monoamine oxidase A inhibitor moclobemide and placebo. Acta Psychiatr Scand 1993; 88: 372-80 21. Dilsaver SC, Qamar AB, Del Medico VJ. The efficacy of bupropion in winter depression: results of an open trial. J Clin Psychiatry 1992; 53: 252-5 22. Partonen T, Lonnqvist J. Moclobemide and fluoxetine in treatment of seasonal affective disorder. J Affect Disord 1996; 41 (2): 93-9 23. Lam RW, Levitt AJ, Levitan RD, et al. The Can-SAD Study: a randomized controlled trial of the effectiveness of light therapy and fluoxetine in patients with winter seasonal affective disorder. Am J Psychiatry 2006; 163 (5): 805-12 24. Frank E, Prien RF, Jarrett RB, et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991; 48: 851-5 25. Parikh SV, Lam RW. Clinical guidelines for the treatment of depressive disorders: I. Definitions, prevalence, and health burden. Can J Psychiatry 2001; 46 Suppl. 1: 13-20S

This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. Acknowledgements

Dr Westrin is funded by a fellowship award from Lund University Medical Faculty, Region Sk˚ane and Ellen och Henrik Sj¨obrings Minnesfond, and has no conflicts of interest that are directly relevant to the content of this review. Dr Lam is on speaker/advisory boards for, or has received research funds from, ANS, Inc., AstraZeneca, Biovail, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, Eli Lilly, GlaxoSmithKline, GreatWest Life, Janssen, Litebook Company, Inc., Lundbeck, SanofiAventis, Servier, VGH and UBC Hospital Foundation, and Wyeth. He has stock options in Litebook Company, Inc. No sources of funding were used to assist in the preparation of this review.

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Correspondence: Dr Raymond W. Lam, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 2A1. E-mail: [email protected]

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